Domperidone: ventricular arrhythmia and sudden death (continued)

Translated from Rev Prescrire March 2012; 32 (341): 196-197
Domperidone: ventricular arrhythmia
and sudden death (continued)
Abstract
Domperidone, a ‘’hidden’’ neuroleptic, is used for symptomatic treatment
of gastroesophageal reflux disease,
despite its uncertain efficacy. The intravenous form was withdrawn from the
market in the 1980s following deaths
due to cardiac arrhythmias. QT prolongation leading to cardiac arrhythmias, including life-threatening torsades de pointes, has also been
attributed to oral domperidone.
In 2010, two case-control studies,
one Canadian and one Dutch, showed
that patients who died suddenly or
had severe ventricular arrhythmias
were statistically significantly more
likely than controls to have been
exposed to domperidone.
In practice, given its uncertain efficacy and a disproportionate risk of
sudden death and severe ventricular
arrhythmia, domperidone should not
be used.
roleptic. These warnings were reinforced
in 2011 (9-11), following publication of two
new case-control studies in 2010 (12,13).
Troubling Dutch data. A case-control
study examined a Dutch general practice
database including patients aged 18 years
or over, between 1996 and 2007 (12).
Cases were patients who either died
due to cardiac causes preceded by abrupt
loss of consciousness within one hour
after acute symptom onset, or patients
who died unexpectedly and who had
been stable during the previous 24 hours,
with no evidence of a non-cardiac
cause. 1304 cases of sudden death and
62 cases of severe ventricular arrhythmia
were matched with respectively 13 480
and 634 controls based on age, sex and
date of onset.
The risk of sudden death was about
four times higher among patients taking
domperidone (odds ratio (OR) = 3.7, 95%
confidence interval (95%CI): 1.7 to 8.1),
and daily doses above 30 mg were associated with an 11-fold increase in the risk
(OR = 11.4, 95%CI: 2 to 65) (a,b)(12).
Rev Prescrire 2012; 32 (341): 196-197.
D
omperidone is a “hidden” neuroleptic used for symptomatic treatment of gastroesophageal reflux, nausea
and vomiting (1,2). QT prolongation leading to cardiac arrhythmias, including lifethreatening torsades de pointes, has
been attributed to domperidone (1,3,4).
In 1986, ventricular arrhythmias, that
were sometimes fatal, led to market withdrawal of injectable domperidone. However, oral forms remained on the market.
Domperidone is metabolised by
cytochrome P450 isoenzyme CYP 3A4.
Co-administration with drugs that inhibit
this isoenzyme, such as macrolides and
azole antifungals, can lead to domperidone accumulation causing QT prolongation and cardiac arrhythmias (5-7).
A Dutch case-control study conducted
in 2005 showed that patients who died
suddenly due to cardiac causes were
four times more likely than controls to
have been exposed to domperidone (2,8).
In late 2008, QT prolongation and ventricular arrhythmias were added to the
summaries of product characteristics
(SPCs) for products containing this neu-
Another study in Canada. A Canadian case-control study using a database for the province of Saskatchewan
examined whether sudden death and
severe ventricular arrhythmia were linked
to exposure to domperidone, proton pump
inhibitors or other drugs (13).
Between 1990 and 2005, among the
83 212 patients listed in the database,
1559 patients who died suddenly due to
cardiac causes and 49 patients who
developed severe ventricular arrhythmia
were matched with 6428 controls.
Average age was 79 years, 53% of
patients were women, and 22% were
diabetic. The relative risk of sudden death
or severe ventricular arrhythmia was
about 1.5 times higher among patients
taking domperidone than among those
taking a proton pump inhibitor (OR = 1.44,
95%CI: 1.1 to 1.9) or no medication
(OR = 1.6, 95%CI: 1.3 to 2) (a)(13).
In practice: do not use domperidone. It is unacceptable to expose
patients with simple gastroesophageal
reflux or nausea and vomiting to a risk of
severe ventricular arrhythmia and sudden
death. Domperidone should therefore be
avoided. If lifestyle measures fail to control gastroesophageal reflux, patients
may be prescribed an antacid (taking
care to avoid drug interactions) or a proton pump inhibitor (7).
In addition, domperidone must not be
used to increase milk production in breastfeeding women (14). It is better to discuss
non-drug solutions with patients.
©Prescrire
a- The odds ratio is the ratio between the probability that
an event (e.g. a disease) will occur and the probability that
the same event will not occur (ref 15).
b- According to the French SPC, the daily dose for adults
and children over 12 years of age is 10 to 20 mg of domperidone 3 or 4 times per day, with a maximum dose of
80 mg per day (ref 10).
Selected references from Prescrire’s literature
search.
1- Prescrire Editorial Staff “Domperidone: QT prolongation in infants” Prescrire Int 2011; 20 (112): 14.
2- Prescrire Editorial Staff “Domperidone and sudden death” Prescrire Int 2006; 15 (86): 226.
3- Prescrire Editorial Staff “Severe ventricular
arrhythmia and sudden death on neuroleptics” Prescrire Int 2002; 11 (61): 146-150.
4- “Domperidone”. In: “Martindale The Complete
Drug Reference” The Pharmaceutical Press, London. www.medicinescomplete.com accessed 6 February 2012: 10 pages.
5- Prescrire Rédaction “Fiche P1A. Inhibiteurs et
substrats de l’isoenzyme CYP 3A4 du cytochrome
P450” Rev Prescrire 2011; 31 (338 suppl. interactions
médicamenteuses).
6- Prescrire Editorial Staff “Domperidone and sudden death” Prescrire Int 2008; 17 (94): 67.
7- Prescrire Rédaction “6-1. Patients ayant un reflux
gastro-œsophagien” Rev Prescrire 2011; 31
(338 suppl. interactions médicamenteuses).
8- Straus SMJM et al. “Non-cardiac QTc-prolonging
drugs and the risk of sudden cardiac death” Eur
Heart J 2005; 26: 2007-2012.
9- Prescrire Rédaction “Dompéridone: troubles cardiaques ajoutés dans les RCP de ce neuroleptique”
Rev Prescrire 2009; 29 (313): 821.
10- Agence française de sécurité sanitaire des
produits de santé “Résumé des caractéristiques du
produit-Motilium° 10 mg” 13 January 2011.
afssaps.sante.fr accessed 6 September 2011: 5 pages.
11- EMA “Domperidone and risk of QTc prolongation, serious ventricular arrhythmias and sudden
cardiac death. Final SmPC and PL wording agreed
by PhVWP in October 2011” November 2011.
www.ema.europea.eu accessed 3 December 2011:
1 page.
12- van Noord C et al. “Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands”
Drug Saf 2010; 33 (11): 1003-1014.
13- Johannes CB et al. “Risk of serious ventricular
arrhythmia and sudden cardiac death in a cohort of
users of domperidone: a nested case-control study”
Pharmacoepidemiol Drug Saf 2010; 19 (9): 881-888.
14- Prescrire Rédaction “Pas de dompéridone chez les
femmes allaitantes” Rev Prescrire 2011; 31 (329): 234.
15- Prescrire Rédaction “Glossaire” Rev Prescrire
2011; 31 (333): 545.
PRESCRIRE INTERNATIONAL JULY 2012/VOLUME 21 N° 129 • PAGE 183
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